南方科技大学Ping Gao和中国科学技术大学Huafeng Zhang研究组合作的研究显示，定位于线粒体的环GMP-AMP合酶（cGAS）通过抑制铁死亡促进癌症进展。这一研究成果于2023年3月2日发表在国际学术期刊《细胞研究》杂志上。

研究人员发现cGAS定位于线粒体，并保护肝癌细胞免受体外和体内铁死亡的影响。cGAS锚定在线粒体外膜上，并与动力蛋白相关蛋白1（DRP1）结合以促进其寡聚化。在没有cGAS或DRP1寡聚化的情况下，线粒体ROS会积累并且铁死亡增加，这会抑制肿瘤生长。总的来说，该研究揭示了cGAS在协调线粒体功能和癌症进展方面的未知作用，表明线粒体中cGAS这种相互作用可以作为癌症治疗的潜在靶点。

研究人员表示，cGAS的一个已知功能是识别胞质DNA，这与宿主激活通过干扰素基因（STING）依赖的先天免疫反应对抗病原体有关。最近的进展还发现cGAS可能通过定位到细胞质以外的亚细胞区室而参与几种非感染性反应。然而，尚不清楚cGAS在不同生物学条件下的亚细胞定位和功能;特别是它在癌症进展中的作用。

附：英文原文

Title: Mitochondria-localized cGAS suppresses ferroptosis to promote cancer progression

Author: Qiu, Shiqiao, Zhong, Xiuying, Meng, Xiang, Li, Shiting, Qian, Xiaoyu, Lu, Hui, Cai, Jin, Zhang, Yi, Wang, Mingjie, Ye, Zijian, Zhang, Huafeng, Gao, Ping

Issue&Volume: 2023-03-02

Abstract: A well-established role of cyclic GMP-AMP synthase (cGAS) is the recognition of cytosolic DNA, which is linked to the activation of host defense programs against pathogens via stimulator of interferon genes (STING)-dependent innate immune response. Recent advance has also revealed that cGAS may be involved in several noninfectious contexts by localizing to subcellular compartments other than the cytosol. However, the subcellular localization and function of cGAS in different biological conditions is unclear; in particular, its role in cancer progression remains poorly understood. Here we show that cGAS is localized to mitochondria and protects hepatocellular carcinoma cells from ferroptosis in vitro and in vivo. cGAS anchors to the outer mitochondrial membrane where it associates with dynamin-related protein 1 (DRP1) to facilitate its oligomerization. In the absence of cGAS or DRP1 oligomerization, mitochondrial ROS accumulation and ferroptosis increase, inhibiting tumor growth. Collectively, this previously unrecognized role for cGAS in orchestrating mitochondrial function and cancer progression suggests that cGAS interactions in mitochondria can serve as potential targets for new cancer interventions.

DOI: 10.1038/s41422-023-00788-1

Source: https://www.nature.com/articles/s41422-023-00788-1